2. Academic Validation
  3. Microbial-derived Urolithin A Targets GLS1 to Inhibit Glutaminolysis and Attenuate Cirrhotic Portal Hypertension

Microbial-derived Urolithin A Targets GLS1 to Inhibit Glutaminolysis and Attenuate Cirrhotic Portal Hypertension

  • Cell Mol Gastroenterol Hepatol. 2024 Jul 20;18(4):101379. doi: 10.1016/j.jcmgh.2024.101379.
Rui Li 1,  Zhile Liu 1,  Wensou Huang 1,  Yongjian Guo 1,  Chan Xie 2,  Hongmei Wu 3,  Jianxin Liu 1,  Xiaoyang Hong 1,  Xiaobin Wang 1,  Jingjun Huang 1,  Mingyue Cai 1,  Zhaoxiong Guo 1,  Licong Liang 1,  Liteng Lin 4,  Kangshun Zhu 5
Affiliations

Affiliations

  • 1 Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Interventional Cancer Center, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
  • 2 Department of Infectious Diseases, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3 Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
  • 4 Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Interventional Cancer Center, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. Electronic address: linliteng@yeah.net.
  • 5 Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Interventional Cancer Center, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. Electronic address: zhksh010@163.com.
PMID: 39038605 DOI: 10.1016/j.jcmgh.2024.101379
Abstract

Background & aims: Cirrhotic portal hypertension (CPH) is the leading cause of mortality in patients with cirrhosis. Over 50% of patients with CPH treated with current clinical pharmacotherapy still present variceal bleeding or sometimes death owing to insufficient reduction in portal pressure. Elevated intrahepatic vascular resistance (IHVR) plays a fundamental role in increasing portal pressure. Because of its potent effect in reducing portal pressure and maintaining normal portal inflow to preserve liver function, lowering the IHVR is acknowledged as an optimal anti-CPH strategy but without clinical drugs. We aimed to investigate the protective effect of microbial-derived Urolithin A (UroA) in IHVR and CPH.

Methods: Carbon tetrachloride or bile duct ligation surgery was administered to mice to induce liver fibrosis and CPH. 16S rRNA gene Sequencing was used for microbial analysis. Transcriptomics and metabolomics analyses were employed to study the host and cell responses.

Results: UroA was remarkably deficient in patients with CPH and was negatively correlated with disease severity. UroA deficiency was also confirmed in CPH mice and was associated with a reduced abundance of UroA-producing Bacterial strain (Lactobacillus murinus, L. murinus). Glutaminolysis of hepatic stellate cells (HSCs) was identified as a previously unrecognized target of UroA. UroA inhibited the activity of glutaminase1 to suppress glutaminolysis, which counteracted fibrogenesis and contraction of HSCs and ameliorated CPH by relieving IHVR. Supplementation with UroA or L. murinus effectively ameliorated CPH in mice.

Conclusions: We for the first time identify the deficiency of gut microbial metabolite UroA as an important cause of CPH. We demonstrate that UroA exerts an excellent anti-CPH effect by suppressing HSC glutaminolysis to lower the IHVR, which highlighted its great potential as a novel therapeutic agent for CPH.

Keywords

Glutamine Metabolism; Gut Microbiota; Innovative Therapy; Portal Hypertension; Urolithin A.

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